Altered expression of Alzheimer\u27s disease-related proteins in male hypogonadal mice

Age-related depletion of estrogens and androgens is associated with an increase in Alzheimer\u27s disease (AD) brain pathology and diminished cognitive function. Here we investigated AD-associated molecular and cellular changes in brains of aged hypogonadal (hpg) male and female mice. hpg Mice have a spontaneous, inactivating genetic mutation in the GnRH gene resulting in lifelong deficiency of gonadotropins and gonadal sex hormones. Western blot analysis revealed low levels of amyloid precursor protein and high levels of presenilin 1, amyloid precursor protein C-terminal fragment, and β-amyloid 42 in brains of aged male, but not female, hpg mice. Changes were confined to the hippocampus and were not evident in the cerebellum or other brain tissues. Male hpg mice tended to have lower levels of IL-1β protein than male littermate controls. Immunohistochemical staining of the basal forebrain revealed that male hpg mice had lower choline acetyltransferase levels per neuron compared with controls. These AD-like changes specific to male hpg mice supports a link between androgen depletion and the development of AD pathology

An integrated dyspepsia module for first year Pharmacy students: a flexible and generic template for integrating science with clinical and professional practice

Objective: To design an integrated dyspepsia module for first year pharmacy undergraduates, which combines clinical and professional practice with fundamental sciences, in five different science subject areas, as a prototype for future disease- or system-based integrated modules. Methods: The approaches used in designing this module are described with particular emphases on strategies adopted to integrate science and practice, and the new ways of working adopted by the design team. Students’ views and experiences of the module, and its integration, were explored using questionnaires. Results: A high proportion of students reported positive views and experiences of the module, the integration and its impact (as self-reported) on their learning and practice. The assessment of student performance indicated learning and attainment was at an appropriate level for a first year module. Both the student marks and research results indicate a positive student learning experience. The main activities undertaken whilst designing and developing the module, and the personnel involved are presented, and provide an indication of the staff time and resourcing required in developing this module. Conclusions: The dyspepsia module provides a flexible and effective template for the integration of science and practice in theme-based modules, with students reporting positively about the integration, including their perception of its contribution to improving their learning and understanding. Our experience suggests that new more collaborative ways of working are required when designing integrated modules

An integrated dyspepsia module for first year Pharmacy students: a flexible and generic template for integrating science with clinical and professional practice

Objective: To design an integrated dyspepsia module for first year pharmacy undergraduates, which combines clinical and professional practice with fundamental sciences, in five different science subject areas, as a prototype for future disease- or system-based integrated modules.Methods: The approaches used in designing this module are described with particular emphases on strategies adopted to integrate science and practice, and the new ways of working adopted by the design team. Students’ views and experiences of the module, and its integration, were explored using questionnaires.Results: A high proportion of students reported positive views and experiences of the module, the integration and its impact (as self-reported) on their learning and practice. The assessment of student performance indicated learning and attainment was at an appropriate level for a first year module. Both the student marks and research results indicate a positive student learning experience. The main activities undertaken whilst designing and developing the module, and the personnel involved are presented, and provide an indication of the staff time and resourcing required in developing this module.Conclusions: The dyspepsia module provides a flexible and effective template for the integration of science and practice in theme-based modules, with students reporting positively about the integration, including their perception of its contribution to improving their learning and understanding. Our experience suggests that new more collaborative ways of working are required when designing integrated modules

An interdisciplinary framework for evaluating 19th century landscape paintings for ecological research

As we contemplate the future of forest landscapes under changing climate conditions and land-use demands, there is increasing value in studying historic forest conditions and how these landscapes have changed following past disturbances. Historic landscape paintings are a potential source of data on preindustrial forests with highly detailed, full-color depictions of overstory and understory environments. They display key details about forest community composition, microhabitat features, and structural complexity from a time well before the advent of color photography. Despite these paintings’ potential, their scientific applications have been impeded by questions of validity. How truly accurate are the images portrayed in these paintings? How much of an image is an artist’s manipulation of a scene to best illustrate an allegory or romanticized view of nature? Following an established assessment model from historical ecology for evaluating resource validity, we demonstrate how scholarship on art history can be integrated with ecological understanding of forest landscapes to follow this model and address these questions of image veracity in 19th century American art. Further, to illustrate the potential use of these historic images in ecological studies, we present in a case study assessing microhabitat features of 10 different paintings. While this paper explores 19th century landscape art broadly, we focus our art historical review in particular on Asher Durand, a prolific and influential artist associated with the so-called “Hudson River School” in the mid-1800s. Durand left clear records about his perspectives on accurately depicting nature, and from a review of images and writings of Durand, we find support for the potential use of many of his paintings and sketches in historic forest ecology research. However, we also identify important caveats regarding potential ecological interpretations from these images. More broadly, because 19th century landscape paintings are not always directly transcriptive, and because regional art cultures differed in the 1800s, we cannot within this paper speak about landscape image veracity across all 19th century landscape art. However, in following established methods in historical ecology and integrating tools from art history research, we show that one can identify accurate historic landscape paintings for application in scientific studies

Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1/350 individuals in the United Kingdom. The cause of amyotrophic lateral sclerosis is unknown in the majority of cases. Two-sample Mendelian randomization enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study summary statistics for serum concentrations of 566 metabolites which were population matched with a genome-wide association study of amyotrophic lateral sclerosis. For each metabolite, we performed Mendelian randomization using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction, our unbiased screen revealed three metabolites that were significantly linked to the risk of amyotrophic lateral sclerosis: Estrone-3-sulphate and bradykinin were protective, which is consistent with literature describing a male preponderance of amyotrophic lateral sclerosis and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit the breakdown of bradykinin. Serum isoleucine was positively associated with amyotrophic lateral sclerosis risk. All three metabolites were supported by robust Mendelian randomization measures and sensitivity analyses; estrone-3-sulphate and isoleucine were confirmed in a validation amyotrophic lateral sclerosis genome-wide association study. Estrone-3-sulphate is metabolized to the more active estradiol by the enzyme 17β-hydroxysteroid dehydrogenase 1; further, Mendelian randomization demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17β-hydroxysteroid dehydrogenase 1, modify risk for amyotrophic lateral sclerosis. Finally, in a zebrafish model of C9ORF72-amyotrophic lateral sclerosis, we present evidence that estradiol is neuroprotective. Isoleucine is metabolized via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction that consumes vitamin B12. Multivariable Mendelian randomization revealed that the toxic effect of isoleucine is dependent on the depletion of vitamin B12; consistent with this, rare variants which reduce the function of MMUT are protective against amyotrophic lateral sclerosis. We propose that amyotrophic lateral sclerosis patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12

Dyspnea-related cues engage the prefrontal cortex - evidence from functional brain imaging in COPD

Dyspnea is the major source of disability in chronic obstructive pulmonary disease (COPD). In COPD, environmental cues (e.g. the prospect of having to climb stairs) become associated with dyspnea, and may trigger dyspnea even before physical activity commences. We hypothesised that brain activation relating to such cues would be different between COPD patients and healthy controls, reflecting greater engagement of emotional mechanisms in patients. Methods: Using FMRI, we investigated brain responses to dyspnea-related word cues in 41 COPD patients and 40 healthy age-matched controls. We combined these findings with scores of self-report questionnaires thus linking the FMRI task with clinically relevant measures. This approach was adapted from studies in pain that enables identification of brain networks responsible for pain processing despite absence of a physical challenge. Results: COPD patients demonstrate activation in the medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC) which correlated with the visual analogue scale (VAS) response to word cues. This activity independently correlated with patient-reported questionnaires of depression, fatigue and dyspnea vigilance. Activation in the anterior insula, lateral prefrontal cortex (lPFC) and precuneus correlated with the VAS dyspnea scale but not the questionnaires. Conclusions: Our findings suggest that engagement of the brain's emotional circuitry is important for interpretation of dyspnea-related cues in COPD, and is influenced by depression, fatigue, and vigilance. A heightened response to salient cues is associated with increased symptom perception in chronic pain and asthma, and our findings suggest such mechanisms may be relevant in COPD

A new mechanism for Cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models

Background and Purpose: Epidiolex, a form of highly purified cannabidiol (CBD) derived from Cannabis plants has demonstrated seizure control activity in patients with Dravet syndrome, without a fully elucidated mechanism of action. We have employed an unbiased approach to investigate this mechanism at a cellular level. Experimental Approach: We use a tractable biomedical model organism, Dictyostelium, to identify protein controlling the effect of CBD and characterize this mechanism. We then translate these results to a Dravet Syndrome mouse model and an acute in vitro seizure model. Key Results: CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human GCSH protein, which is functionally linked to folate one-carbon metabolism (FOCM). Analysis of FOCM components identified a mechanism for CBD in directly inhibiting methionine synthesis. Analysis of brain tissue from a Dravet syndrome mouse model also showed drastically altered levels of one-carbon components including methionine, and an in vitro rat seizure model showed an elevated level of methionine that is attenuated following CBD treatment. Conclusions and Implications: Our results suggest a novel mechanism for CBD in the regulating methionine levels, and identify altered one-carbon metabolism in Dravet syndrome and seizure activity. voltage-dependent anion selective channel proteins, VDAC1

Long-Term Gene Therapy Causes Transgene-Specific Changes in the Morphology of Regenerating Retinal Ganglion Cells

Recombinant adeno-associated viral (rAAV) vectors can be used to introduce neurotrophic genes into injured CNS neurons, promoting survival and axonal regeneration. Gene therapy holds much promise for the treatment of neurotrauma and neurodegenerative diseases; however, neurotrophic factors are known to alter dendritic architecture, and thus we set out to determine whether such transgenes also change the morphology of transduced neurons. We compared changes in dendritic morphology of regenerating adult rat retinal ganglion cells (RGCs) after long-term transduction with rAAV2 encoding: (i) green fluorescent protein (GFP), or (ii) bi-cistronic vectors encoding GFP and ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) or growth-associated protein-43 (GAP43). To enhance regeneration, rats received an autologous peripheral nerve graft onto the cut optic nerve of each rAAV2 injected eye. After 5–8 months, RGCs with regenerated axons were retrogradely labeled with fluorogold (FG). Live retinal wholemounts were prepared and GFP positive (transduced) or GFP negative (non-transduced) RGCs injected iontophoretically with 2% lucifer yellow. Dendritic morphology was analyzed using Neurolucida software. Significant changes in dendritic architecture were found, in both transduced and non-transduced populations. Multivariate analysis revealed that transgenic BDNF increased dendritic field area whereas GAP43 increased dendritic complexity. CNTF decreased complexity but only in a subset of RGCs. Sholl analysis showed changes in dendritic branching in rAAV2-BDNF-GFP and rAAV2-CNTF-GFP groups and the proportion of FG positive RGCs with aberrant morphology tripled in these groups compared to controls. RGCs in all transgene groups displayed abnormal stratification. Thus in addition to promoting cell survival and axonal regeneration, vector-mediated expression of neurotrophic factors has measurable, gene-specific effects on the morphology of injured adult neurons. Such changes will likely alter the functional properties of neurons and may need to be considered when designing vector-based protocols for the treatment of neurotrauma and neurodegeneration

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Summary Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886) we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralising antibody titres (NAbT) using a live virus microneutralization assay against wild-type (WT), Delta, Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titres and T cell responses after the fourth vaccine dose increases compared to those after the third vaccine dose. Patients who received B cell-depleting therapies within 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination